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Salvia Divinorum Presentation Part II

As I men­tioned before, I got to give a 10 minute present­a­tion on Salvia divinorum to my phar­ma­co­logy class. It went down pretty well, so I thought I’d write it up for you guys! Clicking on any slide will open it full size in a new window/​tab.

The first thing you should know about Salvia Divinorum is that it’s a very potent hal­lu­cinogen. I mean, realllly potent. It’s name dir­ectly trans­lates to “Sage of the Seers” or “Diviner’s Sage”, so already we know it’s gonna be cool. Salvia Divinorum is a member of the mint family, along with other common herbs, such as basil, rose­mary and garden sage. In fact, Salvia is the Sage genus, which includes the common sage as well as S. Divinorum. This plant is native to one region only — the Oaxaca [“wahaka”] province of Mexico, where it grows best in a moist, shady environment.

Salvia Divinorum found extensive use among the Mazatec, the indi­genous people of this region. Their reli­gion is a blend of tra­di­tional super­sti­tion and a flavour of Chris­tianity (also super­sti­tion!) brought over by the Spanish con­quista­dors. They make extensive use of the natural psy­cho­active plants and fungi in their rituals, including Salvia Divinorum, Morning Glory seeds and psilo­cybin mush­rooms. Salvia in par­tic­ular was used very much as a learning tool to facil­itate visions, par­tic­u­larly in the context of healing or divin­a­tion (hence the name).

Salvia was also a common medi­cine, pre­scribed for such ail­ments as diarrhoea, head­aches and rheum­atism. It was also the number one cure for a semi-​​magical disease known as “panzón de borrego”, or swollen belly.It’s no sur­prise to see a dif­fer­ence in use between the Mazatec and the “west”. The majority of use in the USA, UK and other developed nations is for recre­ation, while the Mazatec adopt a some­what more “respectful” approach. Tra­di­tion­ally, salvia leaves were chewed, or an extract was pre­pared by crushing the leaves and con­suming the liquid. There is no indic­a­tion the plant was ever smoked by these people, which makes sense — the active com­pound has a very high vapor­isa­tion tem­per­ature. It is only the western world who smoke high powered extracts though a bong with a tur­bo­flame lighter!

The effects are many and varied, depending greatly on the amount con­sumed. Uncon­trol­lable laughter is perhaps the most obvious effect, but it doesn’t happen to everyone. Other effects include remem­bering past memories, dis­so­ci­ation of the body and mind, a sen­sa­tion of a force or pres­sure pushing or pulling on the body, usually in a par­tic­ular dir­ec­tion, per­ceiving mem­branes or films or mul­tiple small tiles cov­ering sur­faces and merging with, or becoming other objects. This is in no way com­par­able to any of the classic hal­lu­cino­gens, such as LSD or Mes­calin in effect or dur­a­tion, as the Salvia exper­i­ence usually lasts 15 to 60 minutes.

The active com­pound of Salvia Divinorum is Salvinorin-​​A, a diter­pine com­pound. I know what you’re thinking — “why should I care?” — well, you should! Salvinorin-​​a is the only known psy­cho­active diter­pene AND the first non-​​alkaloidal (or non-​​nitrogenous) hal­lu­cinogen to be dis­covered. It acts as an agonist at the kappa opioid receptor, which is also unusual. The other, clas­sical hal­lu­cino­gens work at the 5-​​HT2a receptor, and the other opioid receptor ligands tend to be alkaloids.

Shown here is a receptor selectivity profile, com­paring the LSD in red with salvinorin-​​a in green. As you can see, the salvinorin-​​a is very selective for the kappa opioid receptor and not a lot else, while LSD shows activity across mul­tiple receptors.

Shown here is the pro­posed kappa receptor:salvinorin-a binding complex, pro­duced from various muta­gen­esis studies.An active dose of salvinorin-​​a can be as low as 200 micro­grams, around the same as LSD, making it one of the most potent hal­lu­cino­gens. But, as I’ve already men­tioned, the exper­i­ence usually lasts under an hour. Salvinorin-​​A does not remain in the body for long, with a half life of between 20 to 80 minutes in non­human primates.

So, an inter­esting drug, but is it also inter­esting clin­ic­ally? Def­in­itely! First off, salvinorin-​​a has shown promise in anal­gesia (pain relieving) studies in mice. Salvinorin-​​a, when injected intraperi­ton­eally, pro­duced an increased tail flick latency in these mice. The tail flick test is designed to measure the pain threshold — the mouses tail is laid out flat on a plate, and at one point along the plate, a beam of light is focused on the plate from under­neath, cre­ating a hot spot under­neath the end of the mouses tail. As soon as the mouse begins to notice any pain, it flicks its tail to the side, so an increase in this amount of time shows an increased pain threshold. This anti­no­ciceptive effect is abol­ished if the mice are first pre-​​treated with a kappa ant­ag­onist, or are genet­ic­ally engin­eered to lack kappa receptors, which proves salvinorin-​​a acts on these receptors in vivo as well as in vitro, shown by the pre­vious graph. To make sure this effect was con­sistent and really did show an increased res­ist­ance to pain, other assays, such as the hot­plate and chemo-​​nociceptive acetic acid abdom­inal con­stric­tion assays were done and pro­duced results con­cordant with analgesia.

As I men­tioned before, Salvia was admin­istered by the Mazatec for diarrhoea, but it has now been shown to prevent myen­teric cholin­ergic trans­mis­sion in the small intest­ines of a guinea pig, effect­ively stop­ping muscle contraction.

Salvia may also shed some light on depres­sion. Other kappa selective agon­ists typ­ic­ally produce depressive like beha­viour in animal models, and salvinorin-​​a seems to produce a similar response. This sup­ports the hypo­thesis that kappa opioid receptor sig­nalling plays a role in depressive beha­viours, but there has been at least one case report where salvia divinorum was used to treat refractory depres­sion — depres­sion that responds to nothing else. Before we can con­clude any­thing from this, further work, including clin­ical trials must be under­taken. Either way, inter­esting stuff!

As we’ve seen, salvinorin-​​a is a bit strange, offering us an exciting new molecule to play around with. Already, chem­ical tweaking of the molecular struc­ture has given us a selective agonist for the mu receptor and further research might lead to many novel, receptor-​​specific compounds.

Salvia has also shed some light on kappa receptors and their role in hal­lu­cin­atory dis­eases. If the kappa agonist, salvinorin-​​a is able to produce such intense hal­lu­cin­a­tions (proving the involve­ment of kappa receptors in mod­u­lating our per­cep­tion), could a kappa ant­ag­onist help reduce hal­lu­cin­a­tions in dis­eases with prom­inent per­cep­tual dis­turb­ances, such as Alzheimer’s or Schizo­phrenia? There are many avenues Salvia Divinorum could lead us down, but if one thing’s for certain, more research is needed!

There are some great papers here, all of which I’d recom­mend, but if you can’t be bothered, there’s a bril­liant TV doc­u­mentary on there, Sacred Weeds. Def­in­itely worth a watch. Thanks!

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2 Responses to Salvia Divinorum Presentation Part II

There is also some spec­u­la­tion that salvia may yield com­pounds in the treat­ment of AIDS and cancer. I was sur­prised you only focused on Salvinorin-​​A in your present­a­tion. Other Salvinorins, –B, –C, etc. Have been dis­covered as well. Also, several Divinorums. It appears some of these other com­pounds may mit­igate or mod­u­late the effects of Salvinorin– A.

All this stuff seems to be 4⁄5 years old, does everything on here still apply? what dif­fer­ences are there now in 2013, has the research moved on? watching TV the other day (the Wright show) they were dis­cussing an article which said that brain dis­eases such as Parkinson’s etc could be cured by 2017, is this true and has it got any­thing to do with the topics dis­cussed above?